Many body organs, except muscles and bones, are situated in a body cavity lined with a mesothelium such as the peritoneal cavity, the thoracal cavity, and the cavity surrounding the heart, the brain and spinal cord. These are virtual cavities, with a small amount of fluid constituting a specific fluid microenvironment and with a mesothelium layer playing an active role in regulating transport of fluid and substances between the fluid of this cavity and the blood while helping the organs to glide in this cavity. The importance of this gliding is obvious for moving organs as bowels, heart and lungs.
In order to perform surgery in such a body cavity, the cavity has to be opened in order to create a working space. The microenvironment thus is disturbed and the mesothelial cell layer is exposed to rinsing liquids and to a gas environment which can be air in open surgery of CO2 during laparoscopic surgery. In order to create an adequate working space during laparoscopic abdominal surgery the pressure has in addition to be increased above the atmospheric pressure by at least 5 to 10 mm of Hg and generally 15 mm of Hg. Higher pressures are avoided out of fear of gas embolism although this limit has not been substantiated clinically.
Surgery with opening of a body cavity is associated with postoperative pain and with adhesion formation.
Best documented is adhesion formation occurring in over 50% of women following abdominal surgery. These adhesions remain a major clinical problem since they cause chronic pain, infertility, and the need for re-interventions. It is estimated that 30% of all infertilities, 30% of chronic pain, and 100% of bowel obstructions in women are caused by adhesions. Following surgery some 30% of women have to undergo repeat surgery of which 6% is directly and 29% indirectly related to adhesions, which increase the difficulty and complication rate of these surgeries as described by Lower, A. M. et al. in “Adhesion-related readmissions following gynaecological laparoscopy or laparotomy in Scotland: an epidemiological study of 24 046 patients.” Hum. Reprod. 2004; 19, 1877-1885.
Postoperative pain is less understood. The somatic pain of the skin and other incisions is caused immediately by nerve lesions and subsequently by the inflammatory reaction, which is necessarily associated with the healing process. Visceral pain, e.g. from the pelvic cavity, on the contrary is known to be different. The nociceptors are specific. At rest nerve activity is low and most of the nociceptors are sleeping until activated. This explains that bowel movements are not painful under normal condition. Visceral pain moreover is more stretch than trauma related and proportional to the sum of neural firing activity and thus poorly localized with referred pain and often associated with vasomotor symptoms. Infection recruits and activates these nociceptors explaining that during peritonitis even bowel movements become extremely painful.
Prevention of postoperative pain does not yet exist and treatment is limited to the use of pain killers. There are no data describing the mechanism or the prevention of recruitment and/or activation of these nociceptors by the acute surgical trauma and the acute inflammation.
Prevention of postoperative adhesions has been limited to the suggested good surgical practice with gentle tissue handling and to barriers keeping injured areas separated for at least 5 days. This treatment was based upon the observations that surgical trauma is followed by an inflammatory reaction, with exudation and fibrin deposition and a well-known cascade of events leading either to healing within a few days or to adhesion formation. If the fibrin is rapidly removed by fibrinolysis, the entire area of trauma, irrespective of the area is healed within a few days, since proliferation of mesothelial cells starts from multiple areas. If the healing process is delayed for whatever reason, the growing fibroblasts or tissue repair cells will use the fibrin as a scaffold leading to adhesion formation. The mechanical separation of injured areas, by resorbable solid membranes or semi-solid gels results in a 40% to 50% reduction of adhesion formation as evidenced by repeat laparoscopy. These studies obviously were done for specific interventions as ovarian surgery and myomectomies only, whereas there are no data for clinically important endpoints as reintervention rate, fertility rates or severity of chronic pain.
The importance of the entire peritoneal cavity and of the specific microenvironment of the peritoneal fluid in postoperative pain and in adhesion formation was described over the last decade, mainly by the group of Philippe Koninckx. Key observations were the observation that manipulation of bowels in the upper abdomen enhanced adhesion formation in the pelvis pointing to substances released into the peritoneal fluid, as described in “Effect of Upper Abdomen Tissue Manipulation on Adhesion formation between Injured Areas in a Laparoscopic Mouse Model” by Shonman et al. in J. Minim Invasive Gynecol. 2009, 16(3) pp 307-312. The second key observation was that surgery is followed by acute inflammation (the phase preceding the inflammatory reaction) of the entire peritoneal cavity and that the severity of this acute inflammatory reaction is proportional to the enhanced adhesion formation, as described by Corona et al in “Postoperative inflammation in the abdominal cavity increases adhesion formation in a laparoscopic mouse model” in Fertil Steril 2011, 95(4) pp 1224-1228. The third observation was that the surgical trauma is essential for adhesion formation but that trauma alone causes quantitatively little adhesions, whereas factors from peritoneal fluid enhance the adhesion formation at the trauma site. The latter, peritoneal cavity enhanced adhesion formation is quantitatively 10 to 20 times more important than the surgical lesion by Koninckx PR et al. e.g. in The role of peritoneal cavity in adhesion formation, Fertil Steril 2011, 96(1) pp 193-197.
Experiments mainly in the mouse model for laparoscopic and for open surgery have delineated a series of good and bad factors enhancing or decreasing adhesion formation probably through acute inflammation. A bad factor is the CO2 pneumoperitoneum through superficial mesothelial hypoxia (defined as less than 10 mm Hg partial pressure) eventually ROS, and this effect is duration and pressure dependent as described by Molinas CR, Mynbaev O, Pauwels A, Novak P, Koninckx PR. In “Peritoneal mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation in a laparoscopic mouse model.”, Fertil Steril 2001; 76:560-567. Equally detrimental is mesothelial hyperoxia, defined as a partial O2 pressure higher than 60 mm of Hg through at least ROS as described by Elkelani, O. A., Binda, M. M., Molinas, C. R. & Koninckx, P. R., in “Effect of adding more than 3% O2 to carbon dioxide PP on adhesion formation in a laparoscopic mouse model.”, Fertil. Steril. 82, 1616-1622 (2004). Also strongly detrimental is desiccation as described by Binda M M, Molinas C R, Hansen P., Koninckx P R. In “Effect of desiccation and temperature during laparoscopy on adhesion formation in mice”, Fertil Steril 2006; 86:166-175, blood especially fibrin and an increased peritoneal temperature. Beneficial factors identified so far are normoxia (defined as a partial oxygen pressure between 10 and 70 mm of Hg, or 2 to 6% of oxygen in the gas used for the pneumoperitoneum, as described in U.S. Pat. No. 6,428,500, cooling the peritoneal cavity with a third means which together with humidifying is protective through cooling and by eliminating any desiccation, as described in U.S. Pat. No. 8,172,788. The single most effective factor is N2O in concentrations of more than 5%, as described in U.S. patent application 2012/0330224. In the presence of 5 to 10% of N2O no or a marginal additive effect of O2 could be demonstrated as shown in FIG. 2.
All factors described as beneficial or detrimental in laparoscopic surgery were equally beneficial and detrimental in open surgery. Besides their effect on adhesion formation, it is not surprising that they were equally effective in reducing or promoting tumor cell implantation, and in, preventing or enhancing CO2 resorbtion during endoscopic surgery as described by Binda M M, Corona R, Amant F, Koninckx P R. in “Conditioning of the abdominal cavity reduces tumour implantation in a laparoscopic mouse model.” Surgery Today 2013; in press. These factors also will prevent the progressively increasing CO2 resorbtion over time during laparoscopic surgery thus permitting surgery of longer duration which can be particularly important in obese patients and for surgery in strong Trendelenburg (FIG. 3). This effect is even more important when oxygenation of underlying tissues is considered. The progressively rising CO2 resorbtion and its prevention over time can only be explained by the fact that the intact mesothelial layer actively prevents diffusion of CO2 gas. Following retraction, diffusion of CO2 gas becomes quantitatively much more important which means that the depth of hypoxia progressively increases from initially some 100 μ to at least 3-4 mm. Hypoxia in deeper layers, albeit only a few mm becomes excessively important when considering thin organs as a bowel wall, especially during and after surgery, or and a remaining ovarian wall after excision of an ovarian cyst. Clinically this indeed translates to bowel perforations and leakage or to a decrease in ovarian reserve, two of the frequent complications of surgery.